The present invention relates to a medicament for the prevention or treatment of fibrosis involving extracellular matrix dysbolism, a pharmaceutical composition for the prevention or treatment of fibrosis involving extracellular matrix dysbolism, and a medicament for alleviation of extracellular matrix dysbolism.
Fibrosis is a disease characterized by excessive deposition of connective tissue-protein involving extracellular matrix dysbolism in the skin and other organs such as the lungs, heart, liver, and kidneys. For example, hepatic fibrosis is a disease characterized by the excessive deposition of collagen and other connective tissue proteins in the liver. Diseases leading to hepatic fibrosis include vairal hepatitis, alcoholic liver disease, schistosomiasis etc. In these diseases, the connective tissue protein gradually accumulates in the hepatic tissue. As a result, disorders in the hepatic functions occur and finally lead to cirrhosis (J. Hepatol. 8, 115, 1989). On the other hand, scleroderma and other skin fibrosis are conditions characterized by the excessive deposition of collagen and other connective tissue protein in the epidermis of the skin. The cause of skin fibrosis includes various skin diseases such as chronic inflammation and chronic autoimmune reactions, and various skin injury such as mechanical wounds and burns (J. Rheumatol. 15, 202, 1988). Further, pulmonary fibrosis is a condition characterized by the excessive deposition of collagen or other connective tissue proteins in the lungs and is induced by pneumonia medicamentosa caused by chemotherapeutic agents such as anti-tumor drugs and antibiotics (Am. J. Pathol. 259, L159, 1990).
The mechanism of pathogenesis of fibrosis have not yet been sufficiently elucidated at the present. In general, the proliferation and function of fibroblasts are closely controlled in normal conditions. However, in pathological state in which inflammation or tissue injury is serious or sustained, the tissue repair mechanism goes into overdrive and the control mechanism is abrogated (Int. J. Biochem. Cell Biol. 29, 79, 1997). Excessive tissue repair is caused by over-production of connective tissue protein probably due to abnormal proliferation of fibroblasts and extracellular matrix dysbolism. The cytokines causing such a phenomenon include, fibroblast growth factor (FGF family), transforming growth factor (TGF-xcex2), platelet derived growth factor (PDGF), etc. (FASEB J. 8, 854, 1994). In recent years, numerous studies have been performed to obtain the substances inhibiting the production or the activity of such cytokines, but no inhibitors have yet been applied to human. Further, anti-inflammatory agents such as steroid have been used to treat fibrosis with the aim of suppressing chronic inflammation, but they cannot be said to be sufficiently satisfactory in terms of efficacy and side effects. A superior medicament for the treatment of fibrogenesis is therefore needed.
On the other hand, chymase is a serine protease stored in mast cell granules, and widely present in tissue such as the skin, heart, vascular walls, intestines, etc. (Mast Cell Proteases in Immunology and Biology; Caughey, G. H., Ed; Marcel Dekker, Inc.; New York, 1995). Numerous findings that suggest chymase is involved in various types of fibrosis have already been reported. For example, it has been reported that administration of cromoglycate, an inhibitor for mast cell degranulation, suppresses skin fibrosis in Tsk (tight skin) mice, an animal model for scleroderma (Am. J. Pathol. 82, 493, 1976) (J. Rheumatol. 14, 299, 1987). Furthermore, it-has been reported that chymase activity is increased in Tsk mice (Jp. J. Pharmacol. 97 (sup. I) 60P, 1998), and that there is a correlation between the severity of the skin fibrosis and the number of skin mast cells in a bleomycin-induced scleroderma model in mice (Clin. Immunol. 92, 6, 1999). Regarding pulmonary fibrosis, in addition, it is known that pulmonary. fibrosis is not induced by administration of bleomycin in mast cell deficient mice, suggesting involvement of mast cells that produce chymase (Agents Actions 39, 20, 1993). Further, regarding hepatic fibrosis, the number of mast cells in human livers increases along with the fibrogenesis of livers (J. Hepatol. 26, 1042, 1997). A similar increase of mast cells is observed even in various hepatic fibrosis models (Hepatology 23, 888, 1996, J. Hepatol. 29, 112, 1998). In biliary cirrhosis model in rat, mast cell degranulation are observed in the liver, showing the involvement of mast cell granular components such as chymase in pathogenesis of fibrosis (Hepatology 23, 888, 1996). Regarding the involvement of chymase in fibrogenesis of the heart, on the other hand, it has been reported that chymase activity is 5-fold in the pressure-overloaded hamster heart in which fibrosis and apoptosis are observed (FEBS lett. 406, 301, 1997). Recently, it has been shown that rat mast cell chymase (RMCP-1) causes apoptosis of cardiomyocytes derived from neonatal rats, suggesting that chymase may play a role in cell death of cardiomyocytes and fibrogenesis during progression of heart failure (Circulation 100, 1443, 1999). Further, it has also been reported that the expression of mRNA of chymase is augmented in the end stage where fibrogenesis becomes prominent in a canine with heart failure induced by rapid right Ventricular pacing (Matsumoto et al., 73rd Scientific Sessions of American Heart Association, November 2000, New Orleans, Abs. 2191). Restenosis following PTCA is a vascular disease associated with fibrosis. It has been reported that an increase in mast cells augmentation of expression of chymase is observed in balloon-injured artery in dog, and that tranilast that inhibits mast cell degranulation suppresses neointima formation in this model (Circulation 99, 1084, 1999). However, there is also a report that bleomycin induced pulmonary fibrosis is, induced even in mast cell-deficient mice in the same way as normal mice (Lab. Invest. 78, 1431, 1998). There are still many unclear points in the role of mast cells or chymase in various types of fibrosis.
There are findings suggesting the mechanism of action of chymase in fibrosis. For example, it has been reported that chymase promotes in culture the production of TGF-xcex2, the major cytokine for fibrogenesis (J. Biol. Chem. 270, 4689, 1995). Further, there is a report that chymase acts in vitro on procollagen, a precursor of collagen, to promote collagen fibril formation (J. Biol. Chem. 272, 7127, 1997) and a report that chymase activates procollagenase (Biochem. J. 305, 301, 1995).
At the present time, a broad search is under way for substances which can inhibit chymase activity in animal models with the aim of elucidating the role of chymase in the body.
There are chymase inhibitors such as low molecular weight chymase inhibitors such as shown in print (Protease Inhibitors; Barrett et al., Eds; Elssevier Science B. V.; Amsterdam, 1996), xcex1-keto acid derivatives reported as peptide type inhibitors (WO93-25574, Proc. Natl. Acad. Sci. USA, 1995, 92, 6738), xcex1,xcex1-difluoro-xcex2-keto acid derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-124691), tripeptide inhibitors (WO93-03625), phosphoric acid derivatives (Oleksyszyn et al., Biochemistry 30, 485, 1991), peptide like inhibitors such as trifluoromethylketone derivatives (WO96-33974, Japanese Unexamined Patent Publication (Kokai) No. 10-53579) and acetoamide derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-7661, Japanese Unexamined Patent Publication (Kokai) No. 10-53579, Japanese Unexamined Patent Publication (Kokai) No. 11-246437, WO99-41277, WO98-18794, WO96-39373), non-peptide type inhibitors such as triazine derivatives (Japanese Unexamined Patent Publication (Kokai) No. 8-208654 and Japanese Unexamined Patent Publication (Kokai) No. 10-245384), phenol ester derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87567), cephem derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87493), isoxazole derivatives (Japanese Unexamined Patent Publication (Kokai) No. 11-1479), imidazolidine derivatives (WO96-04248), hydantoin derivatives (Japanese Unexamined Patent Publication (Kokai) No. 9-31061), quinazoline derivatives (WO97-11941), etc. have been reported, but no satisfactory medicament or treatment method using inhibition of the activity of chymase as a strategy for treatment has yet been established.
The object of the present invention is to provide a side effect-free, safe medicament for prevention or treatment of fibrosis of the skin or various organs, which suppresses the progression of the disease, prevents the progression of complications, and improves the quality of life of the patient.
The present inventors engaged in intensive studies to achieve this object focusing on subcutaneous fibrous layer hypertrophy involving the dysbolism of connective tissue protein and, as a result, found that a chymase inhibitor alleviates the dysbolism of collagen and suppresses the increase in the subcutaneous fibrous layer and thereby completed the present invention.
That is, in accordance with the present invention, there is provided a medicament for the prevention or treatment of fibrosis involving extracellular matrix dysbolism having a chymase inhibitor as an effective ingredient.
In accordance with the present invention, there is also provided a pharmaceutical composition for the prevention or treatment of fibrosis involving extracellular matrix dysbolism including an amount of a chymase inhibitor for alleviating extracellular matrix dysbolism and a pharmaceutically acceptable vehicle.
In accordance with the present invention, the present invention further provides a medicament for alleviating extracellular matrix dysbolism having a chymase inhibitor as an effective ingredient.